1-(N&#39;-(arylalkylaminoalkyl)) aminoisoindoles; a new class of dopamine receptor subtype specific ligands

ABSTRACT

Disclosed are compounds of the formula ##STR1## or the pharmaceutically acceptable salts thereof wherein the 6-membered A ring may be optionally substituted with up to four groups independently selected from halogen, hydroxy, lower alkyl, or lower alkoxy; 
     Ar represents optionally substituted aryl or heteroaryl; 
     Z represents carbon or nitrogen provided that 
     where Z is carbon, R 11  represents hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy, or phenyl optionally substituted with one or two groups selected from hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; and 
     where Z is nitrogen, R 11  represents an electron pair; 
     R 5  is hydrogen or lower alkyl; 
     L and m represent integers; 
     n is 0, or an integer; 
     R 12  and R 13  independently represent lower alkyl; or together may together form an optionally substituted 5-11 membered ring with the nitrogen atoms to which they are bonded; CR&#39;R&#34; represents a methylene group optionally substituted with lower alkyl; and 
     k is an integer of from 1 to 3, 
     which compounds are useful in treating various neuropsychochological disorders including, for example, schizophrenia, dementia, depression, anxiety, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents.

This is a continuation of application Ser. No. 08/463,037 filed Jun. 5,1995, U.S. Pat. No. 5,656,632.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to aminoisoindole derivatives which selectivelybind to brain dopamine receptor subtypes. More specifically, it relatesto 1-(N'-(arylalkylaminoalkyl)) aminoisoindoles and to pharmaceuticalcompositions comprising such compounds. It further relates to the use ofsuch compounds in treating various neuropsychochological disorders.

2. Description of the Related Art

Schizophrenia or psychosis is a term used to describe a group ofillnesses of unknown origin which affect approximately 2.5 millionpeople in the United States. These disorders of the brain arecharacterized by a variety of symptoms which are classified as positivesymptoms (disordered thought, hallucinations and delusions) and negativesymptoms (social withdrawal and unresponsiveness). These disorders havean age of onset in adolescence or early adulthood and persist for manyyears. The disorders tend to become more severe during the patient'slifetime and can result in prolonged institutionalization. Within theUnited States of America, approximately 40% of all hospitalizedpsychiatric patients suffer from schizophrenia.

During the 1950's physicians demonstrated that they could successfullytreat psychotic (schizophrenic) patients with medications calledneuroleptics. This classification of antipsychotic medication was basedlargely on the activating (neuroleptic) properties of the nervous systemby these drugs. Subsequently, neuroleptic agents were shown to increasethe concentrations of dopamine metabolites in the brain. This findingsuggested that altered neuronal firing of the dopamine systemcontributed in some way to the aberrant behavior observed inschizophrenic patients. Additional evidence indicated that dopaminecould increase the activity of adenylate cyclase in the corpus striatum,an effect reversed by neuroleptic agents. Thus, cumulative evidence fromthese and later experiments strongly suggested that the neurotransmitterdopamine was involved in schizophrenia.

One of the major actions of antipsychotic medication is the blockade ofdopamine receptors in brain. Several dopamine systems appear to exist inthe brain and at least five classes of dopamine receptors appear tomediate the actions of this transmitter. These dopamine receptors differin their pharmacological specificity and were originally classified onthe basis of their ability to bind various dopaminergic ligands.

The butyrophenones are a class of drugs containing many potentantipsychotic drugs. Perhaps the most prominent member of this class ofcompounds is the antipsychotic drug haloperidol (chemical name).Haloperidol binds relatively weakly at the major dopamine receptorsubtype which activates adenylate cyclase (commonly classified as the D₁dopamine receptor). In contrast, haloperidol displayed binding affinityat a dopamine receptor subtype which suppressed the activity ofadenylate cyclase (commonly classified as D₂ receptors) in thesubnanomolar range.

Recently, three additional dopamine receptor subtypes have beenidentified using the often congruent sciences of receptor pharmacologyand molecular biology. These new dopamine receptors have been labeled asD3, D4, and D₅. The D₃ and D₄ subtypes are pharmacologically related tothe D₂ receptor via their ability to suppress the activity of adenylatecyclase. Conversely, the D₅ receptor is classified as a "D₁ -like"dopamine subtype through its ability to stimulate cyclase activity.

Recently, a new group of drugs (such as sulpiride and clozapine) havebeen developed with a lesser incidence of extrapyramidal side effects(EPS) than classical neuroleptics. In addition, there is some indicationthat they may be more beneficial in treating negative symptoms in somepatients. Since all D₂ blockers do not possess a similar profile,hypotheses underlying the differences have been investigated. Majordifferences have been detected in the anticholinergic actions of thesedrugs. It has also been suggested that the dopamine receptors in motorareas may differ from those in the limbic areas which are thought tomediate the antipsychotic responses. The existence of the D₃, D₄ and D5and other as yet undiscovered dopamine receptors may contribute to thisprofile. Some of the atypical compounds possess similar activity at D₂,D₃ and D₄ receptors. The examples of this patent fall into this generalclass of molecules.

Using molecular biological techniques it has been possible to clonecDNAs coding for each of the pharmacologically defined receptors. Thereare at least two forms of D1 which have been identified as D₁ and D₅,and two forms of D₂, identified now as D2 and D₄ dopamine receptors. Inaddition, there is at least one form of D₃ dopamine receptor. The1-(N'-(arylalkylaminoalkyl))aminoisoindoles of this invention possessdifferential affinities for each receptor subtype.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula 1 which interact withdopamine receptor subtypes.

The invention provides pharmaceutical compositions comprising compoundsof Formula 1. The invention also provides compounds useful in treatingaffective disorders such as schizophrenia and depression as well ascertain movement disorders such as Parkinsonism. Furthermore, compoundsof this invention are useful in treating the extrapyramidal side effectsassociated with the use of conventional neuroleptic agents. Sinceparticularly dopamine D₃ and D₄ receptor subtypes are concentrated inthe limbic system (Taubes, Science 265 (1994) 1034), which controlscognition and emotion, compounds which interact with these receptors areuseful in the treatment of cognitive disorders. Such disorders may bethe cognitive deficits which are a significant component of the negativesymptoms (social withdrawal and unresponsiveness) of schizophrenia.Other disorders involving memory impairment or attention deficitdisorders can also be treated with some of the compounds of thisinvention that interact specifically with dopamine D₃ and/or D₄ receptorsubtypes. Accordingly, a broad embodiment of the invention is directedto a compounds of Formula 1 ##STR2## where the 6-membered A ring may beoptionally substituted with up to four groups independently selectedfrom halogen, hydroxy, lower alkyl, or lower alkoxy;

Ar represents optionally substituted aryl or heteroaryl;

Z represents carbon or nitrogen provided that

where Z is carbon, R₁₁ represents hydrogen, halogen, hydroxy, loweralkyl, or lower alkoxy, or phenyl optionally substituted with one or twogroups selected from hydrogen, halogen, hydroxy, lower alkyl, or loweralkoxy; and

where Z is nitrogen, R₁₁ represents an electron pair;

R₅ is hydrogen or lower alkyl;

L is an integer of from 1-4;

m is an integer of from 2-5;

n is 0, or an integer of from 1-4;

R₁₂ and R₁₃ independently represent lower alkyl; or together mayrepresent (CR_(x) R_(y))_(s) where s is an integer of from 1-6 and R_(x)and R_(y) independently represent hydrogen or lower alkyl;

CR'R" represents a methylene group optionally substituted with loweralkyl; and

k is 0 or an integer of from 1 to 3.

Thus, the compounds of Formula 1 can be used in the treatment of variousneuropsychochological disorders including, for example, schizophrenia,dementia, depression, anxiety, Parkinson-like motor disorders and motiondisorders related to the use of neuroleptic agents.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can bedescribed by general formula 1: ##STR3## wherein: R₁, R₂, R₃, R₄ and R₇,R₈ and R₉ are the same or different and represent hydrogen, halogen,hydroxy, lower alkyl, or lower alkoxy;

X represents carbon or nitrogen provided that

where X carbon, R₆ represents hydrogen, halogen, hydroxy, lower alkylhaving 1-6 carbon atoms, or lower alkoxy; and

where X is nitrogen, R₆ represents an electron pair;

Y represents carbon or nitrogen provided that

where Y is carbon, R₁₀ represents hydrogen, halogen, hydroxy, loweralkyl, or lower alkoxy; and

where Y is nitrogen, R₁₀ represents an electron pair;

Z represents carbon or nitrogen provided that

where Z is carbon, R₁₁ represents hydrogen, halogen, hydroxy, loweralkyl, or lower alkoxy, or phenyl optionally substituted with one or twogroups selected from hydrogen, halogen, hydroxy, lower alkyl, or loweralkoxy; and

when Z is nitrogen, R₁₁ represents an electron pair;

R₅ is hydrogen or lower alkyl;

L is an integer of from 1-4;

m is an integer of from 2-5;

n is 0, or an integer of from 1-4;

R₁₂ and R₁₃ independently represent lower alkyl; or

R₁₂ and R₁₃ taken together may represent (CR_(x) R_(y))_(s) where s isan integer of from 1-6 and R_(x) and R_(y) independently representhydrogen or lower alkyl;

R₇ and R₈ together may represent a benzo ring optionally substitutedwith up to four substitutents selected from hydrogen, halogen, hydroxy,lower alkyl, or lower alkoxy; and

R₁₄, R₁₅, R₁₆ and R₁₇ are the same or different and represent hydrogenor lower alkyl.

Preferred compounds of Formula 1a are those where s is an integer offrom 1-4, and most preferably from 2-3.

The present invention also encompasses compounds of Formula 2: ##STR4##wherein: R₁, R₂, R₃, R₄ and R₇, R₈ and R₉ are the same or different andrepresent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;

X represents carbon or nitrogen provided that

where X carbon, R₆ represents hydrogen, halogen, hydroxy, lower alkylhaving 1-6 carbon atoms, or lower alkoxy; and

where X is nitrogen, R₆ represents an electron pair;

Y represents carbon or nitrogen provided that

where Y is carbon, R₁₀ represents hydrogen, halogen, hydroxy, loweralkyl, or lower alkoxy; and

where Y is nitrogen, R₁₀ represents an electron pair;

Z represents carbon or nitrogen provided that

where Z is carbon, R₁₁ represents hydrogen, halogen, hydroxy, loweralkyl, or lower alkoxy, or phenyl optionally substituted with one or twogroups selected from hydrogen, halogen, hydroxy, lower alkyl, or loweralkoxy; and

when Z is nitrogen, R₁₁ represents an electron pair;

R₅ is hydrogen or lower alkyl;

L is an integer of from 1-4;

m is an integer of from 2-5;

n is 0, or an integer of from 1-4;

R₁₂ and R₁₃ independently represent lower alkyl; or

R₁₂ and R₁₃ taken together represent (CH₂)_(s) where s is an integer offrom 1-6;

R₇ and R₈ together may represent a benzo ring optionally substitutedwith up to four substitutents selected from hydrogen, halogen, hydroxy,lower alkyl, or lower alkoxy.

Preferred compounds of Formula 2 are those where s is an integer of from1-4, and most preferably from 2-3.

The present invention further encompasses compounds of Formula 3:##STR5## wherein: R₁, R₂, R₃, R₄ and R₇, R₈ and R₉ are the same ordifferent and represent hydrogen, halogen, hydroxy, lower alkyl, orlower alkoxy;

R₁₆ represents hydrogen or lower alkyl;

X represents carbon or nitrogen provided that

where X carbon, R₆ represents hydrogen, halogen, hydroxy, lower alkylhaving 1-6 carbon atoms, or lower alkoxy; and

where X is nitrogen, R₆ represents an electron pair;

Y represents carbon or nitrogen provided that

where Y is carbon, R₁₀ represents hydrogen, halogen, hydroxy, loweralkyl, or lower alkoxy; and

where Y is nitrogen, R₁₀ represents an electron pair;

m is an integer of from 2-5;

R₇ and R₈ together optionally represent a benzo ring optionallysubstituted with up to four substitutents selected from hydrogen,halogen, hydroxy, lower alkyl, or lower alkoxy.

Preferred compounds of formula 3 are those where m is 2, 3 or 4.Particularly preferred compounds of Formula 3 are those where m is 2 or3; R₁, R₂, R₃, R₄ are hydrogen; R₇ and R₉ are hydrogen and R₈ ishydrogen, hydroxy, halogen or alkoxy. More particularly preferredcompounds of Formula 3 are those where m is 2 or 3; R₁, R₂, R₃, R₄ arehydrogen; R₁₆ is hydrogen or methyl; R₇ and R₉ are hydrogen; and R₈ ishydrogen, hydroxy or methoxy. Still other preferred compounds of formula3 are those where m is 2 or 3; X and Y independently represent methyleneoptionally substituted with lower alkyl, preferably methyl; R₁, R₂, R₃,R₄ are hydrogen; R₁₆ is hydrogen or methyl; R₇ and R₉ are hydrogen andR₈ is hydrogen, hydroxy or methoxy.

The present invention also encompasses compounds of Formula 4: ##STR6##wherein: R₁, R₂, R₃, R₄ and R₇, R₈ and R₉ are the same or different andrepresent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;

Y represents carbon or nitrogen provided that

where Y is carbon, R₁₀ represents hydrogen, halogen, hydroxy, loweralkyl, or lower alkoxy; and

where Y is nitrogen, R₁₀ represents an electron pair;

m is an integer of from 2-5; and

R₇ and R₈ together may represent a benzo ring optionally substitutedwith up to four substitutents selected from hydrogen, halogen, hydroxy,lower alkyl, or lower alkoxy.

Preferred compounds of formula 4 are those where m is 2, 3 or 4.Particularly preferred compounds of Formula 4 are those where m is 2 or3; and R₁, R₂, R₃, R₄ are hydrogen; R₇ and R₉ are hydrogen; and R₈ ishydrogen, hydroxy, halogen or alkoxy. More particularly preferredcompounds of Formula 4 are those where m is 2 or 3; and R₁, R₂, R₃, R₄are hydrogen; R₇ and R₉ are hydrogen; and R₈ is hydrogen, hydroxy ormethoxy.

The present invention also encompasses compounds of Formula 5: ##STR7##wherein: R₁, R₂, R₃, R₄ and R₇, R₈ and R₉ are the same or different andrepresent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;

X represents carbon or nitrogen provided that

where X carbon, R₆ represents hydrogen, halogen, hydroxy, lower alkylhaving 1-6 carbon atoms, or lower alkoxy; and

where X is nitrogen, R₆ represents an electron pair;

Y represents carbon or nitrogen provided that

where Y is carbon, R₁₀ represents hydrogen, halogen, hydroxy, loweralkyl, or lower alkoxy; and

where Y is nitrogen, R₁₀ represents an electron pair;

Z represents CH₂ or nitrogen;

m is an integer of from 2-5;

n is 0, or an integer of from 1-4;

R₁₂ represents hydrogen or lower alkyl; and

R₇ and R₈ together optionally represent a benzo ring optionallysubstituted with up to four substitutents selected from hydrogen,halogen, hydroxy, lower alkyl, or lower alkoxy.

Preferred compounds of formula 5 are those where m is 2, 3 or 4 and n is0. Particularly preferred compounds of Formula 5 are those where R₁₂ ishydrogen or alkyl; m is 2, n is 0; Z is CH₂ ; R₁, R₂, R₃, R₄ arehydrogen; R₇ and R₉ are hydrogen; and R₈ is hydrogen, hydroxy, halogenor alkoxy. More particularly preferred compounds of Formula 5 are thosewhere R₁₂ is hydrogen or methyl; m is 2; n is 0; Z is CH₂ ; and R₁, R₂,R₃, R₄ are hydrogen; R₇ and R₉ are hydrogen; and R₈ is hydrogen, hydroxyor methoxy.

In addition, the present invention provides compounds of Formula 6:##STR8## wherein: R₁, R₂, R₃, R₄ and R₈ are the same or different andrepresent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;

R₆ and R₁₀ independently represent hydrogen, halogen, hydroxy, loweralkyl, or lower alkoxy;

Z represents CH₂ or nitrogen;

m is an integer of from 2-5;

R₅ represents hydrogen or lower alkyl;

n is 0, or an integer of from 1-4; and

R₁₂ represents lower alkyl.

Preferred compounds of formula 6 are those where m is 2, 3 or 4 and n is0. Particularly preferred compounds of Formula 6 are those where R₁₂ ishydrogen or alkyl; m is 2, n is 0; Z is CH₂ ; R₁, R₂, R₃, R₄ arehydrogen; and R₈ is hydrogen, hydroxy, halogen or alkoxy. Moreparticularly preferred compounds of Formula 6 are those where R₁₂ ishydrogen or methyl; R₆ is hydrogen; R₁₀ is hydrogen or lower alkoxy,preferably methoxy; m is 2: n is 0: Z is CH₂ ; and R₁, R₂, R₃, R₄ arehydrogen; and R₈ is hydrogen, hydroxy or methoxy.

Representative ##STR9## groups of formula 1 above include the following:##STR10##

Preferred ##STR11## groups of formula 1 above include the following:##STR12##

In the above preferred groups, OR represents hydroxy or alkoxy.

Representative compounds of the present invention, which are encompassedby Formula 1, include, but are not limited to the compounds shown belowin Table 1 and their pharmaceutically acceptable salts. Non-toxicpharmaceutically acceptable salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluene sulfonic, hydroiodic, acetic and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula 1. Those skilled in the art will recognize varioussynthetic methodologies which can be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula 1.

By "aryl" and "Ar" is meant an aromatic carbocyclic group having asingle ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), whichcan optionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By "alkyl" and "lower alkyl" is meant straight and branched chain alkylgroups having from 1-6 carbon atoms.

By "lower alkoxy" and "alkoxy" is meant straight and branched chainalkoxy groups having from 1-6 carbon atoms.

By "heteroaryl" is meant 5, 6, or 7 membered aromatic ring systemshaving at least one hetero atom selected from the group consisting ofnitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridyl,pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl,furanyl, quinolinyl, isoquinolinyl, thiazolyl, and thienyl, which canoptionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By halogen is meant fluorine, chlorine, bromine and iodine.

By alkylsulfonyl is meant a sulfonyl group substituted with a loweralkyl group.

By arylalkylsulfonyl is meant a sulfonyl group substituted with anarylalkyl group.

By aminosulfonyl is meant a sulfonyl group substituted with an aminogroup.

By alkylaminosulfonyl is meant a sulfonyl group substituted with a loweralkylamino, or di-lower alkylamino group.

Representative examples of bridged 4-phenyl-2-aminomethylimidazolesaccording to the invention are shown in Table 1 below.

                  TABLE 1.sup.1    ______________________________________    1 #STR13##    2 #STR14##    3 #STR15##    4 #STR16##    5 #STR17##    6 #STR18##    ______________________________________

The number below each structure is its compound number.

The pharmaceutical utility of compounds of this invention are indicatedby the following assays for dopamine receptor subtype affinity.

Assay for D₂ and D₃ Receptor Binding Activity

Pellets of COS cells containing recombinantly produced D2 or D3receptors from African Green monkey were used for the assays. The sampleis homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 4° C.and pH 7.4. The sample is then centrifuged at 30,000×g and resuspendedand rehomogenized. The sample is then centrifuged as described and thefinal tissue sample is frozen until use. The tissue is resuspended 1:20(wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl.

Incubations are carried out at 48° C. and contain 0.4 ml of tissuesample. 0.5 nM ³ H-YM 09151-2 and the compound of interest in a totalincubation of 1.0 ml. Nonspecific binding is defined as that bindingfound in the presence of 1 mM spiperone; without further additions,nonspecific binding is less than 20% of total binding. The bindingcharacteristics of examples of this patent for the D2 and D₃ receptorsubtypes are shown in Table 2 for Rat Striatal Homogenates.

                  TABLE 2    ______________________________________    Compound Number.sup.1                    D.sub.2 K.sub.i (mM)                              D3 K.sub.i (mM)    ______________________________________    1               2.380     >100    2               1.420     >100    3               1.937     >100    ______________________________________     .sup.1 Compound numbers relate to compounds shown in Table 1 above.

Assay for D₄ Receptor Binding Activity

Clonal cell lines expressing the human dopamine D₄ receptor subtype wereharvested in PBS and the cells centrifuged and the pellets stored at-80° C. until used in the binding assay. The pellets were resuspendedand the cells lysed at 4° C. in 50 mM Tris pH 7.4 buffer containing 120mM NaCl, 1 mM EDTA and 5 mM MgCl₂. The homogenate is centrifuged at48000×g for 10 minutes at 4° C. The resulting pellet is resuspended infresh buffer and centrifuged again. After resuspension of the pellet infresh buffer a 100 ml aliquot is removed for protein determination. Theremaining homogenate is centrifuged as above, the supernatant removedand the pellet stored at 4° C. until needed at which time it isresuspended to a final concentration of 625 mg/ml (250 mg per sample)with 50 mM Tris buffer (pH 7.4) and 120 mM NaCl just prior to use.Incubations were carried out for 60 minutes at 25° C. in the presence of0.1 nM ³ H! YM-09151-2. The incubation was terminated by rapidfiltration through Whatman GF/C filters and rinsed with 2×4 ml washes ofchilled 50 mM Tris (pH 7.4) and 120 mM NaCl. Non-specific binding wasdetermined with 1 mM spiperone and radioactivity determined by countingin an LKB beta counter. Binding parameters were determined by non-linearleast squares regression analysis, from which the inhibition constant Kicould be calculated for each test compound. The binding characteristicsof some examples of this invention are shown in Table 3 for the dopamineD₄ binding assay. In general, compounds of the accompanying Exampleswere tested in the above assay, and all were found to possess a Ki valuefor the displacement of ³ H!YM-09151-2 from the human dopamine D₄receptor subtype of below 500 nM. Some specific data is indicated inTable

                  TABLE 3    ______________________________________    Compound Number.sup.1                    K.sub.i (mM)    ______________________________________    1               0.012    2               0.070    3               0.100    ______________________________________     .sup.1 Compound numbers relate to compounds shown in Table 1 above.

Compounds 1 and 2 are particularly preferred embodiments of the presentinvention because of their profile in binding to dopamine receptorsubtypes.

The compounds of general Formulas 1 may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula 1 and a pharmaceutically acceptable carrier. One or morecompounds of general Formula 1 may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula 1may be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula 1 may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula 1 may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

The compounds of the invention may be prepared by the reactions shownbelow in Scheme 1. Those having skill in the art will recognize that thestarting materials may be varied and additional steps employed toproduce other compounds encompassed by the present invention. ##STR19##where the A ring is as defined above and NR_(a) R_(b) represents thegroup ##STR20## wherein CR'R", k, R₁₁, R₁₂, R₁₃, Ar, and m and n are asdefined above.

The invention is further illustrated by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures and compounds described therein.

EXAMPLE 1

To a solution of trimethyloxonium tetrafluoroborate (2.20 g. 14.9 mmol)in (CH₂ Cl₂, 20 mL) was added a solution of phthalimidine (1.8 g, 13.5mmol) in CH₂ Cl₂ (20 mL) and the solution was stirred for 24 h. Thesolvent was evaporated in vacuo and the residue was dissolved inchloroform (80 mL). To this solution was added1-(aminoethyl)-4-(2-pyrimidinyl)piperazine (2.08 g, 9.0 mmol) followedby triethylamine (5 mL). The solution was boiled under reflux overnightand then the solvent was evaporated in vacuo to afford a semisolidresidue. The residue was dissolved in water (100 mL) and extracted withethyl acetate (3×100 mL) to remove unreacted phthalimidine and primaryamine. The aqueous solution was adjusted to about 20% NaOH by slowaddition of aqueous 50% NaOH and then extracted with chloroform (2×100mL). The combined chloroform extracts were dried (K₂ CO₃) and evaporatedto give Compound 1 as a pale yellow oil (2.9 g, quantitative). Thehydrobromide salt was crystallized from hot ethanol. This compound had amelting point of 292-295° C. (dec.).

EXAMPLE 2

To a solution of trimethyloxonium tetrafluoroborate (1.10 g, 7.45 mmol)in (CH₂ Cl₂, 10 mL) was added a solution of phthalimidine (0.9 g, 6.75mmol) in CH₂ Cl₂ (10 mL) and the solution was stirred for 24 h. Thesolvent was evaporated in vacuo and the residue was dissolved inchloroform (40 mL). To this solution was added3-(aminopropyl)-4-(2-pyrimidinyl)piperazine (1.1 g, 4.5 mmol) followedby triethylamine (5 mL). The solution was boiled under reflux overnightand then the solvent was evaporated in vacuo to afford a semisolidresidue. The residue was dissolved in water (50 mL) and extracted withethyl acetate (3×50 mL) to remove unreacted phthalimidine and primaryamine. The aqueous solution was adjusted to about 20% NaOH by slowaddition of aqueous 50% NaOH and then extracted with chloroform (2×50mL). The combined chloroform extracts were dried (K₂ CO₃) and evaporatedto give Compound 2 as a pale yellow oil (0.75 g, 38%). The hydrobromidesalt crystallized from hot ethanol: mp 149-150° C.; base ¹ H-NMR (CDCl3)8.38 (d, 2H), 7.3-7.5 (m, 5H), 6.55 (t, 1H), 4.62 (s, 2H), 3.9 (m, 4H),3.63 (m, 2H), 2.63 (m, 6H), 1.8 (m, 2H).

EXAMPLE 3

The following compounds are prepared essentially according to theprocedures set forth above in Examples 1 and 2.

(a) 1-(N- 2-{N'-(3-phenylpropyl)-N'-methyl}aminoethyl!)aminoisoindoledioxolate, Compound 3, m.p. 175-177° C.

(b) 1-(N-2-{N'-(3-phenylpropyl)-N'-methyl}aminoethyl!-N-methyl!)aminoisoindole,Compound 4.

(c) 1-(N- 3-{1-(4-(2-pyridyl)piperazinyl)}propylamino!) aminoisoindoledihydrobromide, Compound 5, m.p. 283-285° C. (dec.).

(d) 1-(N- 3-{1-(4-phenylpiperazinyl)}propyl!)aminoisoindoledihydrobromide, Compound 6, m.p. 208-211° C.

(e) 1-(N- 3-{1-(4-(2-methoxyphenyl))piperazinyl}propyl!) aminoisoindoledihydrobromide, Compound 7, m.p. 184-185° C.

(f) 1-(N- 3-{1-(4-phenyl-3-methyl)piperazinyl}propyl!) aminoisoindoledihydrobromide, Compound 8.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention and the manner and process of making and using it are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude the specification.

What is claimed is:
 1. A compound of the formula: ##STR21## or thepharmaceutically acceptable salts thereof wherein: R is hydrogen orlower alkyl;n is 2, 3, 4 or 5; and Z is ##STR22## wherein R₁ is hydrogenor lower alkyl; and R₂ is halogen.